DESCRIPTION: Control of HIV infection in individuals treated with highly active antiretroviral therapy (HAART) is the most effective means for reducing mortality and morbidity of chronically infected individuals. We are now challenged with the goal of functionally curing individuals that have HAART suppressed HIV. The HIV reservoir in HAART treated individuals' remains elusive to our current therapeutic strategies so new strategies are now focused on exploiting the inherent potential of HIV-specific CD8 T cells to target and kill infected cells in order to fully resolve the infection or at least maintain control without the use of HAART. In order to utilize th host repertoire of HIV-specific CD8 T cells to achieve the goal of curing HIV infected individuals, we have to develop strategies that can stably rejuvenate nonfunctional HIV-specific CD8 T cells so that they re-acquire and retain antiviral functions after expansion. To achieve this goal, we have developed a research program that focuses on understanding the mechanism for acquisition and maintenance of acquired gene expression programs in exhausted HIV-specific CD8 T cells. The following aims are designed to identify genes that are targeted for stable epigenetic programming, develop methods for modifying these programs to erase the transcriptional memory of the HIV-specific CD8 T cell, and reactivate the cells in way that facilitates an effective antiviral response during encounter with an HIV-antigen presenting cell. The specific aims of this proposal are: Aim 1. To determine if gene expression program preservation in exhausted HIV-specific CD8 T cells is coupled to maintenance of DNA methylation at transcriptional regulatory regions. a) To identify T-cell exhaustion gene expression programs that are epigenetically preserved following HAART mediated viral control. b) To identify epigenetically poised transcriptional programs in HIV-specific CD8 T cells from HAART treated donors. Aim 2. To identify DNA methylation programs acquired during differentiation of functional HIV-specific CD8 T cells. a) To identify DNA methylation programs specific to functional HIV-specific CD8 T cells in elite controllers. b) To determine if the functional DNA methylation program in EC HIV-specific CD8 T cells is preserved in virus-specific CD8 T cells from other chronic infections. c) To identify the stage of differentiation whe the functional methylation program is lost during progressive exhaustion of HIV-specific CD8 T cells. Aim 3. To determine if modulation of DNA methylation reprogramming of HIV-specific CD8 T cells by ?- chain signaling and PD-1 signal blockade rescues HIV specific CD8 function and killing. a) To determine if IL-15 mediated differentiation of exhausted CD8 T cells results in short and long term heritable changes in gene regulations. b) To determine if inhibition of PD-1 engagement enhances DNA methylation re- programming of HIV-specific CD8 T cells.